MicroRNA-181 Variants Regulate T Cell Phenotype in the Context of Autoimmune Neuroinflammation

Abstract

Background: Recent studies have revealed that multiple sclerosis (MS) lesions have distinct microRNA (miRNA) expression profiles. miR-181 family members show altered expression in MS tissues although their participation in MS pathogenesis remains uncertain. Herein, we investigated the involvement of miR-181a and miR-181b in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE).Methods: miR-181a and -b levels were measured in the central nervous system (CNS) of patients with MS and mice with EAE as well as relevant leukocyte cultures by real-time RT-PCR. To examine the role of the miRNAs in leukocyte differentiation and function, miR-181a and -b mimic sequences were transfected into cultured primary macrophages and purified CD4 + T cells which were then analyzed by RT-PCR and flow cytometry. Luciferase reporter assays were performed to investigate the interaction of miR-181 a and -b with the 3′-UTR of potential target transcripts, and the expression of target genes was measured in the CNS of EAE mice, activated lymphocytes, and macrophages. results: Expression analyses revealed a significant decrease in miR-181a and -b levels in brain white matter from MS patients as well as in spinal cords of EAE mice during the acute and chronic phases of disease. Suppression of miR-181a was observed following antigen-specific or polyclonal activation of lymphocytes as well as in macrophages following LPS treatment. Overexpression of miR-181a and -b mimic sequences reduced proinflammatory gene expression in macrophages and polarization toward M1 phenotype. miR-181a and -b mimic sequences inhibited Th1 generation in CD4 + T cells and miR-181a mimic sequences also promoted Treg differentiation. Luciferase assays revealed Suppressor of mothers against decapentaplegic 7 (Smad7), as a direct target of miR-181a and -b.conclusion: Our data highlight the anti-inflammatory actions of miR-181a and -b in the context of autoimmune neuroinflammation. miR-181a and -b influence differentiation of T helper cell and activation of macrophages, providing potential therapeutic options for controlling inflammation in MS.

Comprehensive microRNA expression profiling in cerebrospinal fluid distinguishes between neurological disease classes

“…For the distinction between CSF taken at initial diagnosis of CIS converters (n = 5) to CIS nonconverters (n = 5), the PAM algorithm identified a 4-miRNA signature (miR-1260, miR-34b, miR-181a, miR-411) with a 100% classification accuracy and an overall error of 0 ( Figure 1E). The CIS/MS signature miRNA miR-181a was previously shown to exert anti-inflammatory effects on T-cell and macrophage differentiation in autoimmune neuroinflammation [9], which explains the differential levels we observed of this miRNA between CIS converters and nonconverters. However, until now the role of miR-34b and miR-411 in the pathogenesis of MS remains unknown.…”

Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn’s Disease

“…The opposite is observed in inflamed tissue. SMAD7 is overexpressed in brain lesions in EAE mice, in human MS [37], and in the intestine of CD patients [38]. Furthermore, in patients with inflammatory bowel disease and high concentrations of SMAD7 in the intestine, an antisense RNA has proven successful against SMAD7 [39][40][41].…”

Environmental Influencers, MicroRNA, and Multiple Sclerosis

“…[108][109][110][111][112][113][114][115][116][117][118][119][120][121][122] MS has been associated with many dysregulated miRNAs with disease modulating effects. 111,117,[123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140] Finding the link between these two groups, environmental factors and miRNAs, may explain the risk of environmental factors on MS pathogenicity. However, only a few researchers have explored the environmental-miRNAs-MS axis.…”